Although morphological evidence suggests that neurodegeneration may have a significant autophagic component, very little is known about the regulation of autophagy in neurons. Additionally, the role of death receptor signaling during neuronal death remains controversial, although it is implicated in inhibiting neuroprotective IGF-I signaling. The proposed research focuses on investigating the role of death receptor signaling and autophagy in the inhibition of IGF-I neuroprotection and the induction of neuronal death. Specific Aim 1: To morphologically and biochemically characterize programmed cell death in Purkinje neurons. Purkinje cell death will be characterized by using pharmacological inhibitors and cellular markers of autophagy. Specific Aim 2: To determine the role of death receptor signaling pathways in Purkinje cell death. Exogenous ligands and dominant interfering receptor fusion proteins will be used to identify the death receptor activated in Purkinje neurons upon trophic factor withdrawal. The signaling pathways downstream of death receptor activation will be elucidated using pharmacological inhibitors, dominant-interfering protein expression and immunocytochemical staining. Specific Aim 3: To determine the mechanism of death receptor-mediated suppression of IGF-I neuroprotection. The components of the IGF-I signaling pathway will be examined using immunocytochemistry, in situ hybridization and overexpression of signaling proteins to determine the impact of death receptor pathways on survival signaling.